Transcription factors are a group of molecules within the cell that function to connect the pathways from extracellular signals to intracellular responses. Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind to specific DNA sequences in the promoter elements of target genes and activate the transcription of these target genes. One family of transcription factors, the ZAS (zinc finger-acidic domain structures) DNA binding protein family is involved in the regulation of gene transcription, DNA recombination, and signal transduction (Mak, C. H., et al. 1998. Immunogenetics 48: 32-39).
Zinc finger proteins are identified by the presence of highly conserved Cys2His2 zinc fingers (Mak, C. H., et al. 1998. Immunogenetics 48: 32-39). The zinc fingers are an integral part of the DNA binding structure called the ZAS domain. The ZAS domain is comprised of a pair of zinc fingers, a glutamic acid/aspartic acid-rich acidic sequence and a serine/threonine rich sequence (Mak, C. H., et al. 1998. Immunogenetics 48: 32-39). The ZAS domains have been shown to interact with the kB like cis-acting regulatory elements found in the promoter or enhancer regions of genes. The ZAS proteins recognize nuclear factor kB binding sites which are present in the enhancer sequences of many genes, especially those involved in immune responses (Bachmeyer, et al. 1999. Nuc. Acid Res. 27, 643-648). The ZAS DNA binding proteins have been shown to be transcription regulators of these target genes (Bachmeyer, et al. 1999. Nuc. Acid Res. 27, 643-648; Wu et al. 1998. Science 281, 998-1001).
The Schnurri family of large zinc-finger proteins consists of three mammalian homologues (Shn1/HIVEP1/MBP-1/PRDII-BF1/ZAS1, Shn2/HIVEP2/MBP-2/ZAS2 and Shn3/HIVEP3/KRC/ZAS3) (Liang, J., et al. (2003). Development 130, 6453-6464; Wu, L. C. (2002). Gene Expr. 10, 137-152) that are distantly related to Drosophila Shn, a protein that acts during embryogenesis as an essential nuclear cofactor for signaling by Decapentaplegic (Dpp), the Drosophila homologue of BMP/TGFβ. The broad expression pattern of the three mammalian Schnurri genes results in overlapping expression in multiple tissue and cell types. However, analysis of individual Schnurri-deficient mice has established that each Schnurri protein possesses unique roles in regulating multiple physiological processes including lymphocyte development, adipogenesis and bone formation.
One member of the mammalian Schnurri family is the zinc finger transcription factor Kappa Recognition Component (KRC) (also known as Shn3, schnurri 3 or Shn3, and human immunodeficiency virus type I enhancer-binding protein 3 (HIVEP3)). Shn3 is a member of the ZAS DNA binding family of proteins (Bachmeyer, et al. 1999. Nuc. Acid Res. 27, 643-648; Wu et al. 1998. Science 281, 998-1001) and has recently been identified as a key regulator of osteoblast function (Jones, et al. (2006) Science 312:1223-1227). Shn3−/− mice exhibit a pronounced high-bone mass phenotype that arises through augmentation of osteoblast synthetic activity. The osteosclerotic phenotype presents postnatally in the Shn3−/− mice, with onset of the phenotype occurring at 3-weeks of age and progressing in magnitude as the mice age.
Another member of the mammalian Schnurri family is Shn2. Shn2 deficiency has been shown to result in an overall reduction of bone remodeling by suppressing both osteoblastic bone formation and osteoclastic bone resorption activities, with a temporally limited mild increase in bone volume/tissue volume in the cancellous bone envelope in the metaphysis of 8- and 12-week-old mice. Shn2 deficiency was also been shown to suppress osterix and osteocalcin expression as well as bone mineralization in vitro (Siata, et al. (2007) J. Biol. Chem., 282:12907-12).
Further elucidation of the factors influencing skeletal patterning and remodeling and the identification of agents capable of modulating these pathways and methods of using such agents would be of great benefit in the treatment of bone disorders.